Glycogen storage disease type 1 (GSD-1) is caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis. We have generated G6Pase- deficient mice and shown that the knockout mice manifest essentially the same pathophysiology as human GSD-1a patients, indicating that the G6Pase-/- mouse is a valid animal model for the study of GSD-1a. To further understand the mode of G6Pase catalysis, we examined G6Pase in the liver and kidney of wild-type and G6Pase knockout mice and demonstrated that G6P transport and hydrolysis are performed by separate proteins which are tightly coupled. Currently, we are pursuing this G6Pase-deficient mouse model to develop gene therapy for GSD-1a. Diagnosis of GSD-1a currently is established by demonstrating the lack of G6Pase activity in the patient's biopsied liver specimen. Our cloning of the G6Pase gene and identification of mutations within the gene that cause GSD-1a allow for the development of a DNA-based diagnostic method. We have characterized the G6Pase gene of 70 unrelated GSD-1a patients and uncovered sixteen disease-causing mutations. This DNA-based diagnosis now permits prenatal diagnosis among at-risk patients and serves as a data-base in screening and counseling patients clinically suspected of having this disease. Methionine adenosyltransferase (MAT) is a key enzyme in transmethylation, transsulfuration, and the biosynthesis of polyamines. We have characterized the human MATA1 gene and shown that individuals deficient in hepatic MAT activity (MAT I/III deficiency) contain mutations in their MATA1 gene encoding the major hepatic forms, MAT I and III. MAT I/III deficiency is characterized by isolated persistent hypermethioninemia and in some cases, unusual breath odor. Several hypermethioninemic individuals have developed abnormal neurological problems including brain demyelination. We demonstrated that the brain demyelination patients are homozygous for MATA1 mutations that generates a truncated MATalpha1 subunit which is enzymatically inactive. We further showed that isolated persistent hypermethioninemia is a marker of MAT I/III deficiency, and that complete lack of MAT I/III activity can lead to neurological abnormalities.